Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. The aim of the present study was to discuss the role of circular RNA (circRNA) dedicator of cytokinesis 1 (DOCK1) in HCC and whether it can affect cell proliferation, invasion and migration by regulating the microRNA (miR)-654-5p/SMAD2 axis. The expression levels of circRNA DOCK1, miR-654-5p and SMAD2 mRNA in HCC cells and transfected Hep3b cells were detected by reverse transcription-quantitative PCR analysis. SMAD2 protein expression levels in HCC cells and transfected Hep3b cells were analyzed by western blot analysis. The viability, proliferation, migration and invasion of transfected Hep3b cells was in turn detected by Cell Counting Kit-8, clone formation, wound healing and Transwell assays. The interaction of circRNA DOCK1 and miR-654-5p, miR-654-5p and SMAD2 was confirmed by the dual-luciferase reporter assay. As a result, the expression of circRNA DOCK1 and SMAD2 was increased, and miR-654-5p was decreased in HCC cells. circRNA DOCK1 directly targeted to miR-654-5p and miR-654-5p directly targeted to SMAD2. Interference with circRNA DOCK1 inhibited the proliferation, invasion and migration of HCC cells by upregulating miR-654-5p expression. The effects of circRNA DOCK1 knockdown could be partially reversed by transfection with a miR-654-5p inhibitor and SMAD2 overexpression. In conclusion, interference with circRNA DOCK1 inhibited proliferation, invasion and migration of HCC cells by regulating the miR-654-5p/SMAD2 axis.